Parkinson's disease results from age-associated neurodegenerative processes leading to a progressive loss of dopamine neurons in the midbrain. Considerable evidence suggests that neurotrophic factors which promote the survival and differentiation of developing neurons also may protect mature neurons from axotomy and neurotoxic damage in vivo. Glial cell line-derived neurotrophic factor (GDNF), a novel member of the TGF-beta superfamily, has been shown to promote survival and morphological differentiation of fetal dopamine neurons in culture and increase dopamine levels and metabolism in adult rats. Therefore, the three parts of this project will investigate a neuroprotective role for GDNF against intranigral and intrastriatal administration of the neurotoxin 6-OHDA, and seek to identify the mechanism(s) underlying this protection. The following hypotheses will be tested: 1) that administration of GDNF prior to an acute intranigral 6-OHDA lesion will protect tyrosine hydroxylase immunoreactive (TH-ir) dopamine neurons in the midbrain. 2) that administration of GDNF prior to a chronic intrastriatal 6-OHDA lesion will protect TH-ir dopamine neurons. 3) that GDNF may exert its protective effects by upregulating the expression of the enzyme, Cu/Zn superoxide dismutase (Cu/Zn SOD), which is designed to protect against cellular oxidative stress. This project will evaluate: (1) the time course of trophic factor protection against neurotoxic injury, (2) behavioral recovery, (3) cell survival of dopaminergic neurons in the substantia nigra and (4) cu/Zn SOD mRNA expression in dopaminergic neurons by using in situ hybridization.